Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines

Haatisha Jandu, Kristina Aluzaite, Louise Fogh, Sebastian Wingaard Thrane, Julie B. Noer, Joanna Proszek, Khoa Nguyen Do, Stine Ninel Hansen, Britt Damsgaard, Signe Lykke Nielsen, Magnus Stougaard, Birgitta R. Knudsen, Jose Moreira, Petra Hamerlik, Madhavsai Gajjar, Marcel Smid, John Martens, John Foekens, Yves Pommier, Nils BrunnerAnne-Sofie Schrohl, Jan Stenvang

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    Abstract

    Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC.Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF 7 and MDA MB 231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump.Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance.Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.
    Original languageEnglish
    Article number34
    JournalB M C Cancer
    Volume16
    Issue number1
    Number of pages13
    ISSN1471-2407
    DOIs
    Publication statusPublished - 2016

    Keywords

    • ABCG2/BCRP
    • Breast cancer
    • Irinotecan
    • Resistance
    • SN-38
    • Topoisomerase I

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